Working Standard

[ajaib5]

I have a reference standard whose potency is determined by potentiometric method. I want to use this reference standard for the standardization of secondary working standard by using HPLC method.

Can I use the potency of reference standard determined by non-specific method like potentiometry? If not then what shall de done?

Do anyone has any answer or any reference available?

Thanks/ Regards

[Mark Tracy]

By "potentiometric" I assume you mean potentiometric titration and not something analogous to pH.

If your active ingredient is a single chemical substance, the answer is relatively easy. Over the range of interest, analyze your standards by both methods and use the reference method to calibrate the HPLC.

If your active ingredient is a mixture of discrete species, you will have a harder task. You need to isolate or purchase each active component and build the correlation for each one. Then you add up the HPLC results for each component, and make sure that it agrees with reference method.

If your active ingredient is an indistinct mixture (say a polymer of some sort) you can treat it as if it were a single substance, but the calibration factor might change for each production batch.

[adam]

Ajaib5

Despite the fact that titrations are inherently non-specific, they are commonly used to determine the assay/purity of a drug substance. ICH guidance Q6A says that, in cases like these, you need to have a selective method to quantify impurities (which is strange because you would always have this anyway).

However, in my opinion titrations are not an acceptable way to determine the purity of a material that will subsequently be used as a standard. The way I've generally seen this handled is that the purity of the original reference material is determined by subtracting the following from 100:

- percent moisture
- percent related substances
- and (if significant) % residual solvents and % heavy metals

This material can then be used as a standard for the assay, or it can be used to determine the purity of a secondary (or working) standard, by HPLC.

[ajaib5]

Thanks for ur reply.

In such case we have decided to determine the chromatographic purity by the HPLC and then subtracting the impurities/sulphated substances/ residual solvents from the chromatographic purity, to ascertain the purity of the compound. The peak purity of the peak should also be checked.

One person also suggested to subtract the impurities/sulphated substances/ residual solvents from the assay determined by the potentiometric titration.

Which will be the better option form these or as suggested by Mr. Adam, any suggestion please.

[oaquattro]

ajaib5

I believe you misunderstood Adam (sorry Adam if I'm wrong)
The fact is that if you test your standard by HPLC with a dispersion of, say, 1%, your uncertainty for two standard deviations (96% probability) will be ±2% and you would start from 98.0 - 102.0 - impurities.

But if you just determine, let's say, 2 impurities of about 0.1% each with a high 25% dispersion!, the uncertainty for each one would be 0.1±0.05%.
Then your final result substracting from 100% would be
100 - 0.2 (±0.1%) = 99.7 - 100.3% in the worst case

Of course you'd also have to substract for loss on drying (water+solvents). I don't believe that heavy metals would have some incidence, unless they are extraordinary high.

And that is really different.
The reason why many people use potentiometric titration for assay plus impurities determination is that the dispersion for potentiometry is typically less than 0.5%, better than that obtained from HPLC, preferably <1% but sometimes <2%.